L-carbalkoxy-x-substituted



' Reissued Aug. 18, 1953 UNITED STATES PATENT OFFICE 1- CARBALKOXY- 4-SUBSTITUTED PIPERAZINES No' Drawing. Original No. 2,535,971, datedDecember 26, 1950, Serial No. 54,816, October 15,

1952, Serial No. 329,153

5 Claims.

Application for reissue December 31,

Matter enclosed in heavy brackets appears in the original patent butforms no part ofthis reissue specification; matter printed in italicsindicates the additions made by reissue.

This invention relates to new organic com pounds and their preparation.More particularly it relates to 1carbalkoxy-i-substituted piperazines.

The l-carbalkoxypiperazines of the present in- .vention may beillustrated by the following general formula:

wherein R and R are members of the group consisting of hydrogen andlower alkyl radicals, R" and R""are hydrogen and aliphatic radicals andX is a member of the group consisting of oxygen, sulfur, and iminoradicals. As used herein, the term "lower alkyl radical means a radicalof 1 to 4 carbon atoms.

In general, the compounds of the present invention are solids, white totan in color. In some cases the compounds may take the form of an oil.The compounds are in general slightly soluble in water but readilysoluble in benzene, lower aliphatic alcohols, isopropyl acetate and thelike. Where X is the imino radical, water soluble addition salts may beformed.

The preparation of the newcompound's of the present invention may beaccomplished in several ways dependent to a large extent on the natureof'the' product desired. We preferto prepare the compounds by reactingal-carbalkoxypiperazine having the formula:

wherein R and R are as previously defined or addition salts of suchpiperazines with any com.- pound which is capable. of introducing intothe 4-position of the piperazine nucleus a group represented by 2city-3,5-dimethylpiperazine, and the like. In a reaction of this typewherein a halogen acid is liberated, it is usually desirable to havepresent an acid binding substance such as an alkali metal bicarbonate,alkali metal carbonate, or the like.

As intermediates to be reacted with the 1- carbalkoxypiperazines, we canuse an alkali metal cyanate or a monoor dialkylcarbamyl chloride to.produce the l-carbalkoxy-4-carbamylpiperazines. In producingl-carbalkoxyi-thiocarbamylpiperazines, we can use as intermediates [analkali metal thiocyanate,] an aliphatic isothiocyanate or a monoordialkylthiocarbamyl chloride. The guanyl derivatives ofl-carbalkoxypiperazines may be prepared by two methods; (1) by thereaction of a l-carbalkoxypiperazine salt with a cyanamide, and (2) bythe reaction of a l-carbalkoxypiperazine with an S-alkylisothioureasalt. A suitable solvent in carrying out either process is water oraqueous alcohol.

The reaction, in. general, is, preferably carried out in solution,although it can be carried out as a fusion process. Temperatures of 20to 110 C. are usually suflicient to complete the reaction in areasonable time when water is used as the solvent. Generally, thereaction is carried out at 20 to about 80 C. when aqueous alcoholicsolvents or hydrocarbon solvents, such as benzene, are used. Theconditions under which the reaction is carried out are dependent bothupon the group being introduced into. the. 4-position and upon thereactivity of the l-carbalkoxypiperazine. [For instance,l-carbethoxypiperazine hydrochloride can be treated in aqueous solution.with potassium thiocyanate at room temperature togive1-carbethoxy-4-thiocarbamylpiperazine; whentrans-l-carbethoxy-2,5-dimethylpiperazine. hydrochloride is treatedvunder similar conditions, no appreciable amount of trans 1 carbethoxy 4thiocarbamyl 2,5-dimethylpiperazine is produced. The latter may beobtained, however, by the heating of trans-1-carbethoxy-2,5-dimethylpiperazine hydrochloride without an added solventin the presencev of potassium thiocyanate to the iusionpoint of themixture] Some of the compounds in the present application are activeantifilarial agents and may be useful in the treatment of filariasis.Other compounds produce sedation in animals stimulated with an agentsuch as ephedrine, and still other compounds show analgesic activity. Ingeneral, the compounds are characterized by their relativelylowtoxicity.

The following examples show in greater detail 3 c the preparation ofillustrative l-carbalkoxylsubstituted piperazines within the scope ofthe present invention.

[Example 1] [To a solution of 19.4 parts of l-carbethoxypiperazine inparts of water is added 9.7 parts of potassium thiocyanate, and thereaction mixture is allowed to stand for about four hours. It is thenevaporated under reduced pressure to a viscous residue. On the additionof 16 parts of absolute ethyl alcohol to the residue, a white solidforms. This solid is separated by filtration and the ethanol filtrate isthen evaporated. On chilling, a solid residue is obtained. The solid isfurther purified by recrystallization from isopropyl acetate. Theproduct, l-carbethoxylthiocarbamylpiperazine, melts at 109.0110.5 0.]

Example 2 A solution of 82 parts of potassium cyanate in '75 parts ofwater is added to a solution of 195 parts of 1-carbethoxypiperazinehydrochloride in 125 parts of water. After standing at room temperaturefor twenty-four hours, the mixture is evaporated to dryness. The residueis extracted with 400 parts of absolute ethanol, acidified withhydrochloric acid and then it is evaporated to about 125 parts ofethanol. On cooling, the product crystallizes from solution. Theprecipitate, after isolation, is further purified by recrystallizationfrom ethanol using activated charcoal. A yield of 146 parts of1-carbethoxy-4-carbamylpiperazine, melting at 161162 0., is obtained.

Example 3 To a solution of 63.3 parts of l-carbethoxypiperazine in 175parts of benzene there is slowly added at -40 0., with cooling andstirring, 34.8 parts of ethyl isothiocyanate. The mixture is stirred atrefluxing temperature for one-half hour. The benzene solution isconcentrated and the product is precipitated by the addition ofpetroleum ether. On recrystallization from a mixture of isopropylacetate and petroleum ether, the product,1-carbethoxy-4-ethylthiocarbamylpiper-azine, melting at 9191.5 0., isobtained.

Example 4 To a solution of 56 parts of trans-l-carbethoxy-2,5-dimethylpiperazine in parts of water is added concentratedhydrochloric acid until the solution is slightly acidic to Congo redpaper. Then 24.3 parts of solid potassium cyanate is added and themixture is stirred until all the potassium cyanate dissolves. Afterstanding, for twenty-four hours, the product is separated by filtration.On crystallization from carbon tetrachloride, the product,trans-1-carbethoxy-4-carbamy1-2,5-dimethylpiperazine, melting at 118.5-119.5 0., is obtained.

The intermediate, trans-1-carbethoxy-2,5-dimethylpiperazine, may beprepared from ethyl chlorocarbonate and trans2,5dimethylpiperazine bythe method described by Moore, Boyle and Thorn, Journal of the ChemicalSociety, 39 (1929). It distills at 112 at 10 mm.

[Example 5] [To a solution of 56 parts oftrans-1-carbethoxy-2,5-dimethylpiperazine in 210 parts of absolute etheris added anhydrous hydrogen chloride until the reaction mixture isacidic to Congo red paper. The hydrochloride salt obtained is isolatedby filtration, ground and mixed well with the evolution of methylmercaptan ceases.

32 parts of potassium thiocyanate. The mixture is then heated at 130 0.for five minutes. The reaction becomes slightly exothermic at about 110C. After cooling, the reaction product is slurried in boiling isopropylacetate, the potassium chloride is removed by filtration and thefiltrate is diluted with petroleum ether. On cooling,trans-1-c'arbethoxy-2,5-dimethyl-4-thiocarbamylpiperazine is obtainedwhich has a meltin point of 94.505 0.]

Example 6 To a solution of 78 parts of ethyl alcohol in parts of Waterare added 41.8 parts of S- methylisothiourea sulfate and 56 parts oftrans- 1-carbethoxy-2,5dimethylpiperazine. The reaction mixture isrefluxed on a steam bath until The reaction mixture is dehydrated byazeotropic distillation with benzene. The resulting solid, trans-1-carbethoxy-2,5-dimethyl 4 guanylpiperazine sulfate, may be furtherpurified by crystallization in the usual manner.

Example 7 N N H N-00Oalky1 wherein R and R are members of the groupconsisting of hydrogen and lower alkyl radicals, R and R are members ofthe group consisting of hydrogen and alkyl radicals, and X is a memberof the group consisting of oxygen, sulfur and imino radicals, and R" andR' are not simultaneously hydrogen when X is sulfur.

2. A l-carbalkoxypiperazine having the general formula:

wherein R" and R' are members of the group consisting of hydrogen andalkyl radicals, and X is a member of the group consisting of oxygen,sulfur and imino radicals, and R and R are not simultaneously hydrogenwhen X is sulfur.

3. A 1-carbalkoxy-4=-dialkylthiocarbamylpiperazine having the generalformula:

in which R" and R are alkyl radicals.

[4. The compound 1-carbethoxy-4-thiocarbamylpiperazine having thefollowing formula:

s ll

5 5. The compound 1-carbethoxy-2,5-dimethyl- 4-guanylpiperazine havingthe following formula:

6. The compound 1-carbethoxy-4-diethy1carbamylpiperazine having thefollowing formula:

\NC- H N-OO0C2H5 C7115 RICHARD JOSEPH TURNER. HUGH WENDELL STEWART.

References Cited in the file of this patent or the original patentUNITED STATES PATENTS 5 Number Name Date Buck Feb. 11, 1947 Buck Feb.11, 1947 Kushner Apr. 19, 1949 Kushner Apr. 19, 1949 Kushner Apr. 19,1949 Steward June 7, 1949

